Metabolomics presents multiple potentially targetable strategies; determining which strategy holds the most promise for response is the goal of Project 1. Cancer cell growth is dependent on nutrient utilization for energy as well as biomass requiring both glucose and glutamine to meet these needs. We show that inhibition of multiple steps in glutamine utilization including directly targeting the mitochondria, preventing glutamine uptake by targeting its membrane transporter, and blocking the necessary conversion of glutamine are all potential treatment strategies. Given multiple possibilities, we believe that a more systematic characterization of metabolic pathways in EAC is necessary. First, we have designed a biomarker-based clinical trial to assess the metabolomic profiles of patients undergoing neoadjuvant therapy for EAC (Specific Research Aim 1). Once dominant pathways are elucidated in patients, we plan to design precision-based, personalized strategies for future clinical trials. Second, despite the dependence on glutamine, EAC is highly glycolytic given that high FDG-PET avidity is almost uniformly present in patients with EAC. Therefore, we explored the link between oxidative phosphorylation (OXPHOS) and glycolysis and determined that thioredoxin interacting protein (TXNIP) is differentially regulated and may serve as a biomarker (Specific Research Aim 2). Lastly, we are testing the mitochondrial targeted drug, MitoVES, which induces apoptosis through mitochondrial outer membrane permeabilization (MOMP) (Specific Research Aim 3).